Coronary artery disease is the leading cause of death in the United States. It is estimated that in excess of 16 million people are living with coronary artery disease (CAD) and more than 1 in three deaths are due to CAD in the US. In addition, more than 1 million people are hospitalized each year in the US because of CAD. The most common form of CAD leads to the narrowing of the coronary arteries (stenosis) resulting in reduced blood flow and oxygen supplied to the heart muscle, results in myocardial ischemia - a condition where the oxygen demand of the myocardium is far in excess of the available supply. The presence of myocardial ischemia is an important risk factor for major adverse cardiac events (MACE: death, myocardial infarction, and stroke). Appropriate early interventions (coronary bypass, angioplasty, pharmacological, or medical therapy) that are guided by the extent and severity of ischemic burden associated with stable CAD may be instrumental in reducing the risk of MACE. Hence a reliable, non-invasive, and repeatable method for determining the extent and severity of ischemia is invaluable in managing patients with CAD. The broad, long-term objective of this proposal is to improve the prognosis of patients with coronary artery disease. An ideal strategy for assessing clinically significant myocardial ischemia would be completely non-invasive; that is, in addition to avoiding the risks of cardiac catheterization, it would be free of ionizing radiation, exogenous contrast media, and pharmacological stress-agents with both risks and side effects. Although the current clinical standards do not provide many of these benefits, a number of these requirements can be met by myocardial Blood-Oxygen-Level-Dependent (BOLD) MRI. However, the widespread use of this approach is currently limited by inadequate sensitivity, specificity, and the need for intravenous pharmacological (adenosine) stress, all of which pose considerable limitations in clinical practice. In the proposed project, we wish to significantly improve the reliability of myocardial BOLD MRI so that is becomes powerful enough to accurately quantify the ischemic volume associated with clinically significant CAD without intravenous pharmacological stress or exogenous contrast media. The proposed method utilizes (i) an individualized targeted change in arterial partial pressure of CO2 (PaCO2) as the non-invasive vasoactive stimulus, (ii) fast, high-resolution, 4D BOLD MRI at 3T and (iii) the generalized linear model (GLM) theory to derive statistical parametric maps (SPM) to reliably detect and quantify the clinically significant ischemic myocardial volume in a data-driven fashion. These studies are expected to provide the fundamental scientific basis for a non-invasive and reliable imaging strategy for evaluating prognosis of patients with coronary artery disease.